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Evidências para utilização dos novos anticoagulantes

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Apresentação em tema: "Evidências para utilização dos novos anticoagulantes"— Transcrição da apresentação:

1

2 Evidências para utilização dos novos anticoagulantes
Celso Arrais Rodrigues Professor Adjunto Disciplina de Hematologia - UNIFESP Hospital Sírio-Libanês – Centro de Oncologia

3 TROMBOEMBOLISMO VENOSO
Complicação frequente e potencialmente grave Localização TVP MMII TEP TVP MMSS TV CEREBRAL INTRA-ABDOMINAIS

4 TEV é a principal causa de morte no mundo
Thrombosis background > mortes/ano1 VTE is a leading cause of death worldwide The European data are taken from the VITAE study, which aimed to estimate the total burden of VTE within the EU per annum.1 An epidemiological model was constructed to estimate the number of venous thromboembolic events, including fatal and non-fatal venous thromboembolic events. Individual models were developed for six EU countries (France, Germany, Italy, Spain, Sweden, the UK) and populated with data from published literature and expert opinions.1 Within the six countries, the estimated total number of VTE-related deaths per year was 370,012. This number was scaled up to take into account the rest of the EU, resulting in an estimated 543,454 VTE-related deaths per year1 The data from the US are from an incidence-based model including hospital- and community­acquired VTE as well as death from recognized and unrecognized VTE.2 The estimated total number of symptomatic venous thromboembolic events in the US was 613,423. There were 296,370 VTE-related deaths annually, of which 294,112 were fatal PE2 References 1. Cohen AT et al. Thromb Haemost 2007;98:756–764 2. Heit JA et al. Blood 2005;106:Abstract 910 mortes/ano2 Mundo ~3 milhões de mortes por ano 1. Cohen AT et al. Thromb Haemost 2007;98:756–764; 2. Heit JA et al. Blood 2005;106:Abstract 910 4

5 TROMBOEMBOLISMO VENOSO
Complicações potencialmente graves/fatais SÍNDROME PÓS-TROMBÓTICA EMBOLIA PULMONAR MACIÇA

6 TROMBOEMBOLISMO VENOSO
Incidência: 1-3:1.000 AUMENTA COM A IDADE Rosendaal F. Hematology (Am Soc Hematol Educ Program). 2005;:1-12.

7 Evolução dos anticoagulantes
2008 2004 2002 1990s Inibidor direto do Xa oral 1980s Inibidor direto de trombina via oral Inibidor Indireto do Xa 1940s Inibidores diretos de trombina 1930s LMWH Antagonistas Da Vitamin K Heparina Xa IIa ATIII (Xa) IIa ATIII (Xa > IIa) II, VII, IX, X (Protein C,S) ATIII (Xa + IIa) *dabigatran 2008

8 Novos anticoagulantes
Anti-FXa Rivaroxaban (o) Apixaban (o) Edoxaban (o) Otamixaban (p) LY (o) DX-9065a (p) Betrixiban (o) TK-442 (o) Anti-Flla (anti-thrombin) Dabigatran (o) Odiparcil (o) Flovagatran (p) Pegmusirudin (p) Peg-hirudin (p) Desirudin (p) O:Oral, P:Parenteral

9 Macrófago Fibroblasto FT TNF-/IL-1 VIIa VII VIIa

10 Macrófago Fibroblasto VIIa FT VII VIIa

11 Macrófago Fibroblasto VIIa FT VII VIIa IIa

12 INICIAÇÃO DA GERAÇÃO DE TROMBINA
II IIa Xa X VIIa Va FT Célula com expressão de FT FT

13 EFEITOS PROCOAGULANTES DA TROMBINA
VIIIa II vWF IIa Xa X VIIa Va vWF VIII FT Célula com expressão de FT V Plaqueta V Va FT

14 AMPLIFICAÇÃO DA GERAÇÃO DE TROMBINA
XI IIa II IX XIa IIa X Xa VIIa Va X FT II Célula com expressão de FT IXa Xa Va VIIIa FT PLAQUETA ATIVADA VIIa X

15

16 Novos Anticoagulantes
VIIa TF INICIAÇÃO X IX Legenda Fator Inativo PROPAGAÇÃO= Fase de geração de trombina Xa Va Complexo Protrombinase IXa Fator Ativo II Protrombina Transformação Reference Kubitza D and Haas S. Expert Opin Investig Drugs 2006;15:843–855 Catálise Rivaroxabana, Apixabana, Edoxabana IIa Trombina Dabigatrana Fibrinogenio Fibrina FORMAÇÃO DO COÁGULO 16 16

17 Comparação dos novos ACOs com a varfarina
Features Warfarin New Agents Onset Slow Rapid Dosing Variable Fixed Indications Same Same Food effect Yes No Drug interactions Yes Yes Monitoring Yes No Half-life Long Short Antidote Yes No

18 Comparação dos novos ACOs com a varfarina
Features Warfarin New Agents Onset Slow Rapid Dosing Variable Fixed Indications Same Same Food effect Yes No Drug interactions Yes Yes Monitoring Yes No Half-life Long Short Antidote Yes No

19 Tratamento da TVP- Guideline CHEST 2012
VKA, LMWH, Rivaroxabana ou Dabigatrana Parenteral * Inicial Long Term Extendida * LMWH, Fondaparinux, UFH 0 a 7 dias 7 dias a 3 meses 3 meses indefinido

20 Características farmacológicas dos novos agentes anticoagulantes
Properties of conventional and new OACs: MoA, PK, PD Características farmacológicas dos novos agentes anticoagulantes Parâmetro Dabigatrana Rivaroxabana Apixabana Edoxabana Alvo Trombina Fator Xa Biodisponibilidade oral 6.5% 80–100% ~66% 50% Dosagem/Administração Fixa, 2x/dia Fixa, 1x/dia Meia-vida (h) 12–14 5–9 (jovens) 11–13 (idosos) 8–13 9–11 Cmax (h) ~6 2–4 1–3 1–2 Monitorização rotineira da coagulação Não Comparison of the pharmacological characteristics of newer oral anticoagulants The four newer OACs in the Phase III stage of development for stroke prevention in patients with AF are: The direct thrombin inhibitor dabigatran The Factor Xa inhibitors: rivaroxaban, apixaban and edoxaban The Factor Xa inhibitors have higher oral bioavailability than the direct thrombin inhibitor dabigatran, which is administered as the prodrug dabigatran etexilate Plasma protein binding for the newer agents ranges from 34% to 95% All the newer OACs can be administered at fixed doses either once or twice daily The half-life of the newer agents ranges from 5 to 14 hours depending on the drug and the patient, and tmax ranges from 1 to 6 hours None of these newer OACs requires routine coagulation monitoring Abbreviation tmax, time to reach maximum plasma concentration References Eriksson BI et al. Annu Rev Med 2011;62:41–57 Frost C et al. J Thromb Haemost 2007;5(Suppl 2):P-M-664 Kubitza D et al. Clin Pharm Ther 2005;78:412–421 Lopes RD et al. Am Heart J 2010;159:331–339 Ogata K et al. J Clin Pharmacol 2010;50:743–753 ROCKET AF Study Investigators. Am Heart J 2010;159:340–347.e1 Ruff CT et al. Am Heart J 2010;160:635–641.e2 Stangier J et al. J Clin Pharmacol 2005;45:555–563 Dabigatran Prescribing information . Available at: 2011/022512s004lbl.pdf. Accessed September 2011 Eliquis Summary of Product Characteristics. Available at: WC pdf. Accessed September 2011 Pradaxa Summary of Product Characteristics. Available at: document_library/EPAR_-_Product_Information/human/000829/ WC pdf. Accessed September 2011 Xarelto Prescribing Information. Available at: Accessed September 2011 Kubitza et al. Eur J Clin Pharmacol ;61:873–880 Raghavan N et al . Drug Metab Dispos 2009;37:74–81 Xarelto Summary of Product Characteristics. Available at: document_library/EPAR_-_Product_Information/human/000944/WC pdf. Accessed September 2011 Eriksson BI et al. Annu Rev Med 2011;62:41–57; Frost C et al. J Thromb Haemost 2007;5(Suppl 2):P-M-664; Kubitza D et al. Clin Pharm Ther 2005;78:412–421; Lopes RD et al. Am Heart J 2010;159:331–339; Ogata K et al. J Clin Pharmacol 2010; 50:743–753; ROCKET AF Study Investigators. Am Heart J 2010;159:340–347.e1; Ruff CT et al. Am Heart J 2010;160: 635–641.e2; Stangier J et al. J Clin Pharmacol 2005;45:555–563; Dabigatran PI; Eliquis SmPc; Pradaxa SmPc; Xarelto PI 20

21 TEP agudo sintomatico com ou semTVP sintomático
Rivaroxaban Xarelto TEP agudo sintomatico com ou semTVP sintomático Estudo EINSTEIN PE Período de tratamento: 3, 6 ou 12 meses Rivaroxabana 15 mg 2x/d Dia 21 Rivaroxabana 20 mg/d Período de observaçao de 30 dias N = 1731 N = 4845 Randomized, open-label, event-driven, non-inferiority study Up to 48 hours’ heparins/fondaparinux treatment permitted before study entry 88 primary efficacy outcomes needed Following randomization, patients allocated to rivaroxaban received a 15 mg bid dose for a total of 3 weeks followed by a 20 mg od rivaroxaban dose Patients allocated to the comparator received enoxaparin twice daily for at least 5 days in combination with VKA and continued treatment with VKA EINSTEIN DVT/PE are multicenter, randomized, open-label, assessor-blind, event-driven, non-inferiority trials for efficacy with a study treatment duration of 3, 6 or 12 months The decision on treatment duration (3, 6 or 12 months) was made by the investigator prior to randomization according to the patient’s risk profile and local standards EINSTEIN DVT/PE Study Information. Accessed 12 November 2010 3 weeks of rivaroxaban 15 mg bid followed by rivaroxaban 20 mg od Two phase II dose-ranging studies performed (ODIXa DVT and EINSTEIN DVT) Efficacy results in rivaroxaban bid and od study arms similar to that in LMWH/VKA comparator arms (both symptomatic recurrent VTE and asymptomatic changes in thrombotic burden) Relative safety in terms of bleeding compared with standard of care control treatment was better for all od regimens as compared with the twice-daily regimen, for which a slightly increased risk of bleeding was demonstrated for the rivaroxaban 20 mg bid and the rivaroxaban 30 mg bid doses Hypothesized that the higher Ctrough levels observed for the twice-daily regimens represented a more intensified anticoagulant effect that could be beneficial in the acute treatment phase A higher asymptomatic improvement rate was observed for the bid dose arms at 3 weeks Based on these clinical observations, it was concluded that the lowest od dose studied (20 mg) should be selected for the EINSTEIN VTE program, with an initial period of 3 weeks of rivaroxaban 15 mg bid EINSTEIN DVT evaluation: The primary objective was to evaluate whether rivaroxaban is at least as effective as enoxaparin/VKA in the treatment of patients with acute symptomatic DVT without symptomatic PE for the prevention of recurrent venous thromboembolic events EINSTEIN PE evaluation: The primary objective is to evaluate whether rivaroxaban is at least as effective as enoxaparin/VKA in the treatment of patients with acute symptomatic PE with or without symptomatic DVT for the prevention of recurrent venous thromboembolic events R N = 1718 Dia 1 Enoxaparina (1.0 mg/kg) 2x/d por pelo menos 5 dias, + AVK ( alvo RNI 2.5, variando entre 2 e 3) N Engl J Med Apr 5;366(14):

22 Tempo para o primeiro evento
3,0 2,5 2,0 1,5 1,0 0,0 0,5 p=0.57 para superioridade HR=1.12; p< (não inferioridade) Rivaroxabana N=2419 Taxa cumulativa de eventos (%) Enoxaparina/AVK N=2413 Tempo para evento (dias) 30 60 90 120 150 180 210 240 270 300 330 360 N Engl J Med Apr 5;366(14):

23 Sangramento clinicamente relevante
HR: 0.90 (0.76–1.07) p=0.23 Enoxaparina/AVK N=2405 15 14 10 13 12 11 9 8 7 6 5 4 3 2 1 Rivaroxabana N=2412 Taxa cumulativa de eventos (%) 30 60 90 120 150 180 210 240 270 300 330 360 Tempo para o evento (dias N Engl J Med Apr 5;366(14):

24 *Some patients had >1 event
Rivaroxaban clinical development Sangramento maior Rivaroxabana (N=2412) Enoxaparina/AVK (N=2405) HR (95% CI) p-value n (%) Sangramento maior* 26 (1.1) 52 (2.2) 0.49 (0.31–0.80) p=0.0032 Fatal 2 (<0.1) 3 (0.1) Retroperitoneal 1 Intracraniano Órgão crítico 6 (0.2) 10 (0.4) 7 (0.3) Intraocular Pericárdico Intra-articular Adrenal Retal/pulmonar/abdominal Queda na hemoglobina 2 g/dl e/ou transfusão 2 unidades 18 (0.7) EINSTEIN PE: principal safety endpoint analysis *Some patients had >1 event Safety population N Engl J Med Apr 5;366(14): 24

25 Taxa cumulativa de eventos (%) Tempo para eventos (dias))
Sangramento Maior HR: 0.49 (0.31–0.80) p=0.0032 3.0 2.5 2.0 1.5 1.0 0.0 0.5 Enoxaparina/AVK N=2405 Taxa cumulativa de eventos (%) Rivaroxabana N=2412 Tempo para eventos (dias)) 30 60 90 120 150 180 210 240 270 300 330 360 N Engl J Med Apr 5;366(14):

26 População frágil Rivaroxabana Enoxaparina/AVK HR 95% CI n (%)
TEV recorrente 14/510 (2,8) 17/477 (3,6) 0,75 (0,37–1,52) Sangramento maior 7/508 (1,4) 24/476 (5,0) 0,26 (0,11–0,61) Sangramento clinicamente relevante 64/508 (12,6) 80/476 (16,8) 0,72 (0,52–0,99) *Pacientes frágeis: idade >75 anos, peso ≤ 50 kg e/ou clearance de creatinina <50 ml/min N Engl J Med Apr 5;366(14):

27 EINSTEIN TVP e EP: Conclusões
Rivaroxabana 15 mg 2x/d por 3 semanas Seguida por Rivaroxabana 20 mg 1x/d TEV Sintomático (TVP ou EP) Eficácia : Não inferior ao HBPM/AVK Segurança : Achados Similares Sangramento Maior: Superioridade para a Rivaroxabana na EP Sem diferença quanto à idade, sexo, peso, Clear Creat, Câncer Reference 1. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. N Engl J Med Dec 23;363(26): N Engl J Med Apr 5;366(14): 27 27 27 27

28 Rivaroxabana: Interações
Indutores fortes da CYP3A4 Fenitoina Rifampicina Carbamazepina Fenobarbital Pode diminuir a concentração plasmática da rivaroxabana. Utilizar com cautela Inibidores fortes da CYP3A4 e P-gp Cetoconazol Itraconazol Voriconazol Posaconazol Ritonavir Contra indicada em uso associado: Anti-micóticos azólicos sistêmicos Inibidores de protease

29 Rivaroxabana e Laboratório
Testes de coagulação não recomendados para a rivaroxabana RNI ( amplifica a variabilidade de resultados) TTPa Esses testes são afetados pela rivaroxabana mas não são adequados para quantificar grandes intervalos de concentração de rivaroxabana ( correlação não linear) Potencial utilidade Tempo de Protrombina Anti fator -Xa Ambos os testes exigem calibradores e controles laboratoriais Tempo de protrombina : alta variabilidade inter-ensaio Baixa sensibilidade para pequenas concentrações Abbreviations HPLC, high-performance liquid chromatography; PiCT, prothrombinase-induced clotting time; TGT, thrombin generation test Reference Lindhoff-Last et al. Ther Drug Monit 2010;32:673–679 Lindhoff-Last et al, 2010

30 Apixaban Eliquis Estudo AMPLIFY: Apixaban (2.5 mg ou 5 mg 12/12) vs. placebo Após 6 a 12 meses de anticoagulação por 1 ano. 2486 pacientes randomizados Frost C, Yu Z, Moore K, Nepal S, Barrett Y, Mosqueda-Garcia R, Shenker A. APIXABAN, AN ORAL DIRECT FACTOR XA INHIBITOR: MULTIPLE-DOSE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS IN HEALTHY SUBJECTS. J Thromb Haemost 2007; 5 Supplement 2: P-M-664 N Engl J Med Feb 21;368(8): Perzborn E, Strassburger J, Wilmen A et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59­7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–521 Depasse F, Busson J, Mnich J et al. Effect of Rivaroxaban – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P1104 Kubitza D, Becka M, Voith B et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59­7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–421 Perzborn E, Strassburger J, Wilmen A et al. Biochemical and pharmacologic properties of Rivaroxaban, an oral, direct Factor Xa inhibitor. Pathophysiol Haemost Thromb 2004;33 (Suppl. 2):Abstract PO079 Fareed J, Hoppensteadt D, Maddenini J et al. Antithrombotic mechanism of action of BAY 59­7939 – a novel, oral, direct Factor Xa inhibitor. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P0518 Kubitza D, Becka M, Mueck W et al. Naproxen has no relevant effect on the safety, tolerability, pharmacodynamics, and pharmacokinetics of Rivaroxaban – an oral, direct Factor Xa inhibitor. Blood 2005;106(11):Abstract 1873

31 Apixaban Eliquis Estudo AMPLIFY: Apixaban (2.5 mg ou 5 mg 12/12) vs. placebo Após 6 a 12 meses de anticoagulação por 1 ano. 2486 pacientes randomizados Frost C, Yu Z, Moore K, Nepal S, Barrett Y, Mosqueda-Garcia R, Shenker A. APIXABAN, AN ORAL DIRECT FACTOR XA INHIBITOR: MULTIPLE-DOSE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS IN HEALTHY SUBJECTS. J Thromb Haemost 2007; 5 Supplement 2: P-M-664 N Engl J Med Feb 21;368(8): Perzborn E, Strassburger J, Wilmen A et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59­7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–521 Depasse F, Busson J, Mnich J et al. Effect of Rivaroxaban – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P1104 Kubitza D, Becka M, Voith B et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59­7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–421 Perzborn E, Strassburger J, Wilmen A et al. Biochemical and pharmacologic properties of Rivaroxaban, an oral, direct Factor Xa inhibitor. Pathophysiol Haemost Thromb 2004;33 (Suppl. 2):Abstract PO079 Fareed J, Hoppensteadt D, Maddenini J et al. Antithrombotic mechanism of action of BAY 59­7939 – a novel, oral, direct Factor Xa inhibitor. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P0518 Kubitza D, Becka M, Mueck W et al. Naproxen has no relevant effect on the safety, tolerability, pharmacodynamics, and pharmacokinetics of Rivaroxaban – an oral, direct Factor Xa inhibitor. Blood 2005;106(11):Abstract 1873

32 Apixaban Eliquis Estudo AMPLIFY: Apixaban (2.5 mg ou 5 mg 12/12) vs. placebo Após 6 a 12 meses de anticoagulação por 1 ano. 2486 pacientes randomizados Frost C, Yu Z, Moore K, Nepal S, Barrett Y, Mosqueda-Garcia R, Shenker A. APIXABAN, AN ORAL DIRECT FACTOR XA INHIBITOR: MULTIPLE-DOSE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS IN HEALTHY SUBJECTS. J Thromb Haemost 2007; 5 Supplement 2: P-M-664 N Engl J Med Feb 21;368(8): Perzborn E, Strassburger J, Wilmen A et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59­7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–521 Depasse F, Busson J, Mnich J et al. Effect of Rivaroxaban – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P1104 Kubitza D, Becka M, Voith B et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59­7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–421 Perzborn E, Strassburger J, Wilmen A et al. Biochemical and pharmacologic properties of Rivaroxaban, an oral, direct Factor Xa inhibitor. Pathophysiol Haemost Thromb 2004;33 (Suppl. 2):Abstract PO079 Fareed J, Hoppensteadt D, Maddenini J et al. Antithrombotic mechanism of action of BAY 59­7939 – a novel, oral, direct Factor Xa inhibitor. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P0518 Kubitza D, Becka M, Mueck W et al. Naproxen has no relevant effect on the safety, tolerability, pharmacodynamics, and pharmacokinetics of Rivaroxaban – an oral, direct Factor Xa inhibitor. Blood 2005;106(11):Abstract 1873

33 Apixaban Eliquis Estudo AMPLIFY: Apixaban (2.5 mg ou 5 mg 12/12) vs. placebo Após 6 a 12 meses de anticoagulação por 1 ano. 2486 pacientes randomizados Frost C, Yu Z, Moore K, Nepal S, Barrett Y, Mosqueda-Garcia R, Shenker A. APIXABAN, AN ORAL DIRECT FACTOR XA INHIBITOR: MULTIPLE-DOSE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS IN HEALTHY SUBJECTS. J Thromb Haemost 2007; 5 Supplement 2: P-M-664 N Engl J Med Feb 21;368(8): Perzborn E, Strassburger J, Wilmen A et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59­7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–521 Depasse F, Busson J, Mnich J et al. Effect of Rivaroxaban – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P1104 Kubitza D, Becka M, Voith B et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59­7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–421 Perzborn E, Strassburger J, Wilmen A et al. Biochemical and pharmacologic properties of Rivaroxaban, an oral, direct Factor Xa inhibitor. Pathophysiol Haemost Thromb 2004;33 (Suppl. 2):Abstract PO079 Fareed J, Hoppensteadt D, Maddenini J et al. Antithrombotic mechanism of action of BAY 59­7939 – a novel, oral, direct Factor Xa inhibitor. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P0518 Kubitza D, Becka M, Mueck W et al. Naproxen has no relevant effect on the safety, tolerability, pharmacodynamics, and pharmacokinetics of Rivaroxaban – an oral, direct Factor Xa inhibitor. Blood 2005;106(11):Abstract 1873

34 para não inferioridade
Dabigatran Pradaxa Estudo RE-COVER - TEV após 9 dias de anticoagulação parenteral Dabigatran VO 150 mg 12/12h vs varfarina (INR ) 2539 pacientes P<0.0001 para não inferioridade Frost C, Yu Z, Moore K, Nepal S, Barrett Y, Mosqueda-Garcia R, Shenker A. APIXABAN, AN ORAL DIRECT FACTOR XA INHIBITOR: MULTIPLE-DOSE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS IN HEALTHY SUBJECTS. J Thromb Haemost 2007; 5 Supplement 2: P-M-664 N Engl J Med Dec 10;361(24): Perzborn E, Strassburger J, Wilmen A et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59­7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–521 Depasse F, Busson J, Mnich J et al. Effect of Rivaroxaban – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P1104 Kubitza D, Becka M, Voith B et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59­7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–421 Perzborn E, Strassburger J, Wilmen A et al. Biochemical and pharmacologic properties of Rivaroxaban, an oral, direct Factor Xa inhibitor. Pathophysiol Haemost Thromb 2004;33 (Suppl. 2):Abstract PO079 Fareed J, Hoppensteadt D, Maddenini J et al. Antithrombotic mechanism of action of BAY 59­7939 – a novel, oral, direct Factor Xa inhibitor. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P0518 Kubitza D, Becka M, Mueck W et al. Naproxen has no relevant effect on the safety, tolerability, pharmacodynamics, and pharmacokinetics of Rivaroxaban – an oral, direct Factor Xa inhibitor. Blood 2005;106(11):Abstract 1873

35 Dabigatran Pradaxa Estudo RE-COVER - TEV após 9 dias de anticoagulação parenteral Dabigatran VO 150 mg 12/12h vs varfarina (INR ) 2539 pacientes P<0.0001 Frost C, Yu Z, Moore K, Nepal S, Barrett Y, Mosqueda-Garcia R, Shenker A. APIXABAN, AN ORAL DIRECT FACTOR XA INHIBITOR: MULTIPLE-DOSE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS IN HEALTHY SUBJECTS. J Thromb Haemost 2007; 5 Supplement 2: P-M-664 N Engl J Med Dec 10;361(24): Perzborn E, Strassburger J, Wilmen A et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59­7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–521 Depasse F, Busson J, Mnich J et al. Effect of Rivaroxaban – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P1104 Kubitza D, Becka M, Voith B et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59­7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–421 Perzborn E, Strassburger J, Wilmen A et al. Biochemical and pharmacologic properties of Rivaroxaban, an oral, direct Factor Xa inhibitor. Pathophysiol Haemost Thromb 2004;33 (Suppl. 2):Abstract PO079 Fareed J, Hoppensteadt D, Maddenini J et al. Antithrombotic mechanism of action of BAY 59­7939 – a novel, oral, direct Factor Xa inhibitor. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, 6–12 August 2005;Abstract P0518 Kubitza D, Becka M, Mueck W et al. Naproxen has no relevant effect on the safety, tolerability, pharmacodynamics, and pharmacokinetics of Rivaroxaban – an oral, direct Factor Xa inhibitor. Blood 2005;106(11):Abstract 1873

36 Dabigatran: Doses aprovadas pelo FDA
150 mg 12/12h 150 mg se CrCl >30 mL / min 75 mg se CrCl mL / min

37 Dabigatran: Laboratório
Monitoração vs. alterações de exames TP TTPa Sem linearidade Não validado para uso TTPa pode ser indicador direto e TT MUITO sensível anti-FIIa cromogênico Hemoclot: teste quantitativo usando o dabigatran como calibrador Ainda não aprovado para uso

38 Hemoclot Assay for Dabigatran
Dabigatran Calibration Curve Dabigatran Treated Patients 50 100 150 200 250 1000 2000 3000 4000 Dabigatran concentration [nM] Hemoclot thrombin clotting time [s] Linear fit ( x) 95% CI 95% Prediction interval (Stangier et al. ISTH 2009, Boston) 38

39 Follow-up :novos anticoagulantes orais
Paciente em Anticoagulação Adesão * Sangramento* Efeitos Colaterais* Exames Laboratoriais ** Medicações concomitantes* Evento Tromboembólico* * Cada Visita ** Hemoglobina, função renal e hepática = anualmente ** ClCr ml/min ou dabigatrana e > 75 anos ou paciente frágil = 6 meses ** ClCr ml/min = 3 meses EHRA practical guide for use of the new oral anticoagulants 2013

40 G. Palareti et al Exp Opin Pharmacot 2013
Situações em que a monitorização laboratorial seria potencialmente útil Situações de emergência Complicações hemorrágicas Indicação de terapêutica trombolítica Necessidade de intervenção cirúrgica Realização de procedimento invasivo Suspeita de overdose G. Palareti et al Exp Opin Pharmacot 2013

41 Novos ACOs: Laboratório

42 Novos ACOs: Laboratório

43 Novos ACOs: Laboratório

44 Novos ACOs: Laboratório

45 Novos ACOs: principais problemas
Sem efeito se esquece de tomar 2% descontinua por intolerância gástrica Sem parâmetros de monitoração Risco de hemorragia em idosos e IRC 5 mortes do Japão com dabigatran Interações medicamentosas Poucos dados sobre substituição de anticoagulantes Sem antídoto específico

46 Novos ACOs: principais problemas
Excluídos de estudos clínicos Idosos, crianças, gestantes Pacientes com HIT TEV não agudo Câncer e doenças crônicas Ainda não seguros em situações frequentes como: Comorbidades IRC grave Insuficiência hepática Doenças digestivas, absortivas Obesidade extrema Interações medicamentosas

47 Xarelto Summary of Product Characteristics
Contra-indicações IRC: não recomendado uso em pacientes com ClCr<30ml/min. Sangramento ativo Hepatopatia associada a coagulopatia e risco de sangramento clinicamente significativo, incluindo pacientes cirróticos Child Pugh B and C. Gestação e Lactação Cardiovascular disease Depression Pain Epilepsy Requiring antibiotics, anti-fungals, anti-malaria drugs Ausência de estudos em: pacientes pediátricos Pacientes com câncer Xarelto Summary of Product Characteristics

48 Manejo do sangramento Manejo dos pacientes com NACO em casos de sangramento Sangramento Grave Risco de morte Sangramento leve Sangramento moderado a grave Tratamento sintomático Compressão mecânica Intervenção cirúrgica Reposição de fluidos Suporte hemodinâmico Transfusão de hemocomponentes Carvão ativado se ingestão < 2h Hemodialise (Dabigatrana) Suporte hemodinâmico e hemostatico Considerar PCC e PCCa (rivaroxaban) FVIIa Postergar a próxima dose ou Suspender a medicação Levy JH et al Anesthesiology 2013; 118:00-00

49 Alternativas com eficácia comprovada no tratamento de TVP/TEP
CONCLUSÕES Novos anticoagulantes disponíveis rivaroxaban, dabigatran e apixaban Alternativas com eficácia comprovada no tratamento de TVP/TEP Não superiores ao tratamento padrão Possível maior segurança pela estabilidade e menos interações Precisam validação em contextos específicos de comorbidades

50 Obrigado!

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